Treatment with different chemotherapeutic agents, such as vincristine, taxol or oxaliplatin, causes in most cases the development of dose-limiting chronic neurotoxicity. The toxic damage is made evident by ensuing neural dysfunctions such as mechanical and cold allodynia, ongoing burning pain, myalgias, tingling, numbness, etc. (Cavaliere R. and Schiff D. 2006, Curr. Neurol. Neurosci. Rep. 6:218-26). The resulting pathological condition is also known as chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN often represents the most important cause of discomfort and suffering in patients undergoing chemotherapy, which strongly limits the practical applicability of the latter. In patients with CIPN symptoms, the interruption of chemotherapy is no valid solution: this exposes to tumour worsening, whereas neurotoxicity is not necessarily removed, as it may persist or even develop after discontinuation of medication. The degree of severity of CIPN depends not only from the drug, time and dose used but also from the total cumulative dose applied.
Depending on the substance used, a pure sensory syndrome (with cisplatin, oxaliplatin, carboplatin) or a mixed sensorimotor neurotoxicity with or without involvement of the autonomic nervous system (vincristine, taxol) can ensue. In addition, the previous administration or co-treatment with two or more neurotoxic agents further increases the incidence and severity of neurotoxic effects. For example, cisplatin alone induced neurotoxic effects in 49% of patients (Bacon M. and et al. 2003, Int. J. Gynecol. Cancer 13:428-34), whereas when co-administered with paclitaxel, sensory neurotoxicity was observed in 91% of patients. These effects may lead to disability and worsening of life quality in the absence of tumor progression and it represents a serious dose-limiting side effect.
In addition, the development of the neurotoxic syndrome can interfere with optimal drug dosing, delay sequencing of therapy, or necessitate the discontinuation of treatment.
Little is known about the mechanism responsible for the development of CIPN and to date no satisfactory therapies are available (Quasthoff S. and Hartung H. P. 2002, J. Neurol. 249:9-17).
Attempts have been made to address the symptoms with drugs efficacious on pain of various origins. For example the tricyclic antidepressant nortriptyline, known to be efficacious in treating pain of different origins and diabetic associated neuropathies, was tested in a double-blind, placebo-controlled trial to establish its ability to treat a cisplatin-induced pain syndrome (Hammack J. E. et al. 2002 Pain 98:195-203). The study included 51 patients and the nortriptyline maximum dose was 100 mg/day. Global statistical analysis of the trial results pointed out the lack of nortriptyline efficacy over placebo. Lamotrigine, a drug that reduces neuronal hyper-excitability, failed to reduce CIPN in phase III clinical trials (Renno S. I. et al. 2006, J. Clin. Oncol. 2006, ASCO Annual Meeting Proceeding Part I Vol 24, No. 18S:8530). All the patients showed severe neurotoxic symptoms induced by treatment with vinca alkaloids (30%), taxanes (25%), platinum-agents (7%), chemotherapy combinations (34%), and others (3%). After 10 weeks of therapy, the average scores were similar between the lamotrigine and placebo treated groups. Gabapentin is an anticonvulsant used for various neuropathies and neuralgias; (Rowbotham M. et al. 1998, JAMA 280:1837-1842; Backonja M. et al. 1998, JAMA 280:1831-1836). This compound, tested on cancer patients with CIPN (Wong G. Y. 2005, J. Clin. Oncol. 2005, ASCO Annual Meeting Proceeding Part I Vol 23, No. 16S:8001), failed to reduce pain intensity (NRS score), sensory neuropathy (ECOG rating), and other adverse events. In addition, patients treated with gabapentin reported significant more adverse side effects such as nystagmus and dizziness. Imidazole derivatives with general nootropic activity have been described in WO 2004/085438; these compounds were not used in association with chemotherapeutic agents and no neuroprotection or other beneficial effect in CIPN has been disclosed.
As summarised above, no effective therapy is currently available for chemotherapy-induced neurotoxicity. The need is thus felt for effective therapies in the treatment of CIPN. A particular need is that of a curative treatment, i.e. capable to treat the underlying cause, as the mere symptomatic treatment has so far failed to obtain appreciable results. The need is also felt for agents capable to improve the tolerability of chemotherapeutic therapy, thereby increasing the clinical acceptance of the latter. A further need is that of suitable co-therapies capable to positively synergise in the effective treatment of cancer, whereby the neurotoxic side-effects of chemotherapeutic agents are inhibited. It is also desired to dispose of pharmaceutical compositions suitable for co-therapy, whereby one agent inhibits the neurotoxic effect of the chemotherapeutic agent. A further need is that of agents capable to block neurotoxic effects of CIPN developing even after discontinuation of the chemotherapeutic agent.